HIV-1 RT is a key enzyme responsible for viral replication and subsequent perpetuation of viral infection. Hence, it has been the primary target for therapeutic intervention against HIV-1 infection. However, rapid emergence of drug-resistant viral strains harboring enzymatically-active mutant RT with reduced drug-sensitivity has frustrated all efforts to control the spread of HIV-1 infection. The mechanism of resistance to nucleoside inhibitors seems to be quite complex since a number of mutational sites do not cluster around the putative dNTP-binding pocket in the polymerase cleft. However, for nonnucleoside RT inhibitors (NNRTIs), a common hydrophobic binding region is seen in the crystal structures of RT liganded with these inhibitors. The side chains of a number of hydrophobic residues located in the fingers, palm and thumb subdomains in the p66 subunit converge to form a hydrophobic NNRTI binding pocket. Any mutational change in these hydrophobic residues reduces the drug-sensitivity due to alteration in the NNRTI-binding pocket. Our proposal seeks to address this problem by developing a group of new NNRTIs which are effective against both the wild type and common drug-resistant variants of HIV-1 RT. Using a combination of structure-based molecular modeling and in vitro assays, we have selected four distinct lead compounds from a large repertoire of compounds displaying inhibitory activity against both wild type and mutant RT. We plan to further modify these lead compounds by a structure-based design strategy to improve their inhibitory potential followed by synthesis and in vitro anti-HIV-1 RT screening. PUBLIC HELATH RELEVANCE: The major focus of this proposal is to develop a new class of NNRTIs that is equally effective against both the wild type and drug-resistant variants of HIV-1 RT. We selected four nonnucleoside lead compounds from a large repertoire of compounds based on structure-based modeling and in vitro anti- RT activity against both the wild type HIV-1 RT and drug-resistant RT mutants. These initial lead compounds will be modified to further enhance their anti-RT activity.